Introduction: 'Early-onset' studies have shown that symptomatic response often occurs early and that early symptomatic response is predictive for later outcome. Limiting factors of these studies include the restriction on symptomatic outcome, the inclusion of mostly moderately ill patients, and the use of various antipsychotics.Methods: Response and remission rates were assessed in 528 severely ill patients with schizophrenia at baseline, week 2,4 and 12 using PANSS, SWN-K, CGI-S, and SOFAS. The clinical measures were combined to one outcome criterion (Com-bOut). Predicitive validity was analyzed for Com-bOut using linear regression models.Results: Rate and time to response differed markedly between outcome measures. 32% reached positive symptom response at week 2, 58% at week 4 and 85% at week 12. Non-response at week 4, but not at week 2 was predictive for later non-response. The combined outcome criterion was best predicted by early response in subjective wellbeing (T=-7.88, p < 0.001) and social functioning(T=-7.43, p < 0.001).Discussion: Rate and time to response might depend on sample characteristics and outcome measure. In severely ill patients early antipsychotic response is possibly delayed from the first 2 to the first 4 weeks. Early response in subjective wellbeing and social functioning are strong predictors for overall outcome, which make them a useful supplementation to the assessment of symptomatic response.

Objective. - The primary objective of this randomised, active-controlled, parallel group, double-blind study was to evaluate the tolerability of treatment with either amisulpride or risperidone in elderly patients with schizophrenia aged over 65 years; evaluation of efficacy was a secondary objective.Methods. - The study included patients of either sex. aged 65 years or older fulfilling DSM IV-diagnostic criteria for psychotic disorders and who presented psychotic symptoms severe enough to require antipsychotic medication. Subjects were randomly allocated to a flexible dose of either amisulpride (100-400 mg/day) or risperidone (1-4 mg/day) for six weeks following a three- to six-day placebo wash-out period. Safety assessment involved adverse event reporting, physical examination, blood pressure, heart rate and ECG monitoring, and laboratory tests. Extrapyramidal symptoms were evaluated with the Simpson-Angus Scale, Barnes Akathisia Scale and the AIMS. Efficacy parameters were changes in score on the PANSS, BPRS, CDS and MMSE scores.Results. - Thirty-eight patients were randomised, 25 to amisulpride and 13 to risperidone. A total of 26 adverse events were experienced by 10 patients in the amisulpride group and five patients in the risperidone group. One patient in each group discontinued the study due to the emergence of a movement disorder. Changes in scores on the three measures of extrapyramidal symptoms were similar in the two groups. The PANSS total score decreased by 27.8% in the amisulpride group and by 29% in the risperidone group between inclusion and study end.Conclusion. - Amisulpride and risperidone are generally well tolerated in elderly patients with schizophrenia. Both drugs appeared to be efficacious in this study population, with no differences in efficacy being observed. However, the sample size was too low to reveal potential inter-group differences. Both these atypical antipsychotics thus appear to be suitable for the treatment of schizophrenia in the elderly. (C) 2008 Elsevier Masson SAS. All rights reserved.

Abstract Because of a unique pharmacodynamic profile, amisulpride seems appropriate for treatment of elderly patients with schizophrenia. In a large-scale naturalistic therapeutic drug monitoring study, daily amisulpride dose, trough and dose-corrected amisulpride plasma levels, co-medication, clinical effectiveness (CGI) and side effects (UKU) were compared between age groups in 395 patients with schizophrenia or schizoaffective disorder (46% women; mean age 39.1 ± 14.2 years, range 18–83 years) under amisulpride therapy. Mean amisulpride doses (574 ± 269 mg/day), plasma levels (304 ± 274 ng/mL), dose-corrected amisulpride plasma levels (C/D ratios, 0.52 ± 0.41 ng/mL:mg), clinical response (at least moderate improvement, 71.6%), and side effects (any side effect, 32.2%; extrapyramidal symptoms, 14.9%) were comparable between age groups ( P > 0.25). At higher age, significantly more benzodiazepines ( P = 0.04), non-benzodiazepine hypnotics ( P = 0.004) and non-psychotropic medications ( P < 0.0001) were prescribed. The naturalistic study showed higher C/D ratios in women ( P = 0.019) and a slight increase of C/D ratios with age ( P = 0.026), but no substantial age-dependent effects on amisulpride doses or plasma levels. In patients above 60 years, clinical response was associated with lower amisulpride plasma levels ( P = 0.016) at comparable doses. Neither the age-dependent decrease of amisulpride clearance nor the significantly higher prevalence of co-morbidity and co-medication seem to be the reasons for definite clinical concerns against amisulpride treatment of elderly if contraindications are seriously taken.

Objective: Studies of subjective wellbeing (SW) in schizophrenia have missed to define and to assess rate and predictors of SW response (SW‐res) and SW remission (SW‐rem). Method: A total of 727 patients with schizophrenia and severely impaired SW at entry (Subjective Wellbeing under Neuroleptics Scale, short version, SWN‐K, total score ≤60) were treated with amisulpride over 12 weeks. SW‐res was defined as SWN total score increase of at least 20% and by at least 10 points and SW‐rem as total score of ≥80 points. Results: Seventy percent fulfilled the SW‐res criterion at week 4. At week 4 and week 12 (endpoint), the SW response criterion distinguished between patients with or without later SW remission and overall symptomatic and functional response. While 39% fulfilled the SW‐rem criterion at endpoint, only 9.1% without early SW‐res were in SW‐rem at follow‐up. Regression analyses indicated that SW‐res was mainly predicted by greater severity of positive symptoms at baseline and SW‐rem by lower severity of negative symptoms and better social functioning, and particularly by early SW‐res. Conclusion: Patients with a risk of SW non‐remission need to be identified early with subsequent treatment adaptation according to recommendations for incomplete remission and treatment resistance in schizophrenia.

Évaluer l’adéquation entre les pratiques de prescription en conditions réelles et les recommandations internationales pour des sujets hospitalisés pour la première fois pour un épisode psychotique.Ont été inclus des sujets hospitalisés pour la première fois en psychiatrie pour un trouble psychotique dans 10 secteurs girondins. Les données recueillies concernant les médicaments ont porté sur les traitements prescrits pendant la première hospitalisation et au cours des deux ans de suivi.L’étude a porté sur 86 patients. L’initiation du traitement neuroleptique a été faite avec un antipsychotique de seconde génération pour 80 % des patients lors de la prescription hospitalière initiale (sédatifs exclus). Toutefois 25 % de patients ont reçu un neuroleptique conventionnel au cours de la première hospitalisation, et 30 % au cours des deux années de suivi (sédatifs exclus). Les co-prescriptions de neuroleptiques observées chez un tiers des sujets étaient liées à l’association d’un neuroleptique sédatif à un antipsychotique ou un neuroleptique conventionnel. Les doses de neuroleptiques prescrites étaient plus élevées que celles recommandées pour un premier épisode.La recommandation internationale principale concernant l’utilisation en première ligne d’antipsychotiques de seconde génération a été suivie pour la plupart des patients. Cependant, il paraît nécessaire d’optimiser les pratiques de prescription, notamment en termes de posologie et de co-prescription.The aims of this pharmacoepidemiological study were to describe the antipsychotic medication received during the first admission and over a two-year follow-up in subjects with a first episode of psychosis, and to assess whether the prescriptions in naturalistic conditions were in adequacy with guidelines.All first-admitted patients, less than 50 years old, consecutively hospitalised in 10 acute wards of two psychiatric hospitals serving Bordeaux's catchment area were included over a period of one year, if they presented with at least one overt psychotic symptom during the last month. Information on psychotropic medication received during the first admission was collected in medical records, and that received after the first admission was collected at the end of a two-year follow-up using multiple sources of information.Of the 86 patients included in the cohort, 53 presented with broadly defined schizophrenia and 33 with psychotic mood disorder. All except two subjects were prescribed at least one neuroleptic drug. Antipsychotic drugs (amisulpride, olanzapine, risperidone, clozapine) were the most frequently prescribed drugs during the first admission and over the two-year follow-up. If sedative neuroleptics were excluded, antipsychotic drugs were the first prescribed neuroleptic drugs in a large proportion (80 %) of patients. Although few patients were first prescribed a conventional neuroleptic, the proportion of subjects treated with these drugs increased over the next prescriptions, and one out of three patients was prescribed at least one of these drugs during the follow-up. The mean dose of antipsychotic drugs at first discharge was higher than that recommended in first episode patients (amisulpride 616 mg, olanzapine 13 mg, risperidone 7 mg). Coprescription of neuroleptic drugs, found in one third of patients at all times of assessment, was especially due to coprescription of a sedative neuroleptic to a conventional or an antipsychotic one. Nearly half of the patients did not take any psychotropic medication at the end of the follow-up.The main recommendation specifying that the first neuroleptic treatment in subjects with a first episode of psychosis should use antipsychotic drugs instead of conventional neuroleptics was generally respected in this cohort of first-admitted subjects with psychosis. However, conventional neuroleptics were found in first or second rank prescriptions, although they should not be used before at least the third rank. The recommendations that the initial neuroleptic dose should be lower in subjects with a first episode, and that coprescription of neuroleptics should be avoided, were frequently not respected. This study highlights the fact that international guidelines should be better applied in naturalistic conditions, and that clinicians have to be better informed about these recommendations.

Whether and how working memory disrupts or alters auditory selective attention is unclear. We compared simultaneous event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) responses associated with task-irrelevant sounds across high and low working memory load in a dichotic-listening paradigm. Participants performed n-back tasks (1-back, 2-back) in one ear (Attend ear) while ignoring task-irrelevant speech sounds in the other ear (Ignore ear). The effects of working memory load on selective attention were observed at 130–210 ms, with higher load resulting in greater irrelevant syllable-related activation in localizer-defined regions in auditory cortex. The interaction between memory load and presence of irrelevant information revealed stronger activations primarily in frontal and parietal areas due to presence of irrelevant information in the higher memory load. Joint independent component analysis of ERP and fMRI data revealed that the ERP component in the N1 time-range is associated with activity in superior temporal gyrus and medial prefrontal cortex. These results demonstrate a dynamic relationship between working memory load and auditory selective attention, in agreement with the load model of attention and the idea of common neural resources for memory and attention.

INTRODUCTION It is assumed that female and male schizophrenic patients respond differentially to acute and chronic treatment with antipsychotics because of pharmacokinetic and pharmacodynamic factors linked to hormonal and constitutional gender differences. However, to date no empirical evidence exists in support of this notion. METHODS In a naturalistic clinical study, we investigated gender differences in a sample of schizophrenic inpatients with acute exacerbation treated with the atypical antipsychotic amisulpride, a selective dopamine D2/D3 receptor antagonist with proven antipsychotic efficacy. Prescribed amisulpride dose, plasma level, clinical response (CGI), and side effects (UKU) were assessed in 99 patients (62 % male, age 18-66 years) under antipsychotic monotherapy with amisulpride at daily doses > or = 400 mg. RESULTS Female patients were significantly older (38.5 +/- 11.8 years) than male patients (32.3 +/- 10.9 years; P = 0.01). Prescribed amisulpride doses were comparable for men (673 +/- 216 mg) and women (665 +/- 229 mg). However, dose-corrected steady-state amisulpride plasma levels (men 0.41 +/- 0.31 ng/mL/mg; women 0.60 +/- 0.39 ng/mL/mg; P = 0.007) were significantly higher in female patients even after age adjustment. No significant differences between men and women emerged with respect to clinical response (77 % vs. 79 %, respectively) and the occurrence of any side effect (41 % vs. 37 %, respectively). DISCUSSION Except for higher dose-related plasma amisulpride levels in women, the explorative study unveiled no clinically relevant gender-specific aspects regarding prescribed dose, effectiveness, and side effects.

Objectives: Amisulpride is an unique neuroleptic drug insofar as it has a dual pharmacodynamic effect. At low doses it blocks selectively presynaptic autoreceptors, and at high doses it blocks postsynaptic D-2/D-3 receptors. This allows the dosage to be adjusted and the treatment tailored to various clinical situations. It is unknown whether this pharmacological property has any hearing for routine treatment. The questions are: which dosages of amisulpride are chosen by physicians in the treatment of schizophrenic inpatients and does this dosage handling deviate from prescription guidelines?; which factors can explain dosage selection, and what is the treatment outcome with different dosages? The study pertains to drug management and dosage finding as principal factors in explaining positive and negative medication results.Methods: In a drug utilization observation study the prescribing of amisulpride for 811 schizophrenic inpatients from 240 psychiatric hospitals was monitored for 8 weeks. Standardized assessment included dosage, the positive and negative symptom scale (PANSS), the clinical global impression rating (CGI), the patients' subjective reaction to amisulpride, psychosocial functioning, EPS and other adverse events. The mean observation period was 49 days.Results: The mean initial daily dose of amisulpride was 361 mg/day. The mean daily dose at day 56 was on average 550 (SD 266) mg/d, ranging from 100 mg to 1600 mg. 17.9% of patients received a maximum dose up to 399 mg/d, 48.1% between 400 and 799 mg/d, and 25.5% 800 mg/d and higher. Higher doses were preferably prescribed for males, patients with involuntary admission, patients with paranoid schizophrenia with acute exacerbation, high CGI and high PANSS-positive scores. Patients with higher doses of amisulpride at the same time received higher rates of additional other neuroleptic drugs. Higher doses yield better results in very severe cases.Conclusions: Prescribed dosages were in the lower range of what is recommended for acute cases. Dosage was significantly influenced by the severity of the illness. Polypharmacy was the rule rather than the exception. Efficacy rates under conditions of routine care were similar to the results from controlled clinical trials, which speaks for their generalizability. Very severe cases profit from higher doses. Copyright (C) 2004 John Wiley Sons, Ltd.

In schizophrenia, stereotypy is observed, a symptom characterized by repetitive, functionless motor behaviour. Whereas cognitive dysfunctioning is known to remain stable throughout the illness, less is known about the course of the motor symptoms. The Zeigeversuch [Mittenecker, E., 1953. Perseveration und Persönlichkeit: 1. Teil: experimentelle Untersuchungen. Z. Exp. Angew. Psychol. 1, 5–31], which entails the generation of a random sequence of button presses, was claimed to capture stereotypy. We used a newly designed computerized version of the Zeigeversuch, the Stereotypy Test Apparatus (STA) to evaluate the evolution of STA performance through the course of the illness.To assess stereotyped and perseverative behaviour, 58 schizophrenic inpatients and 48 healthy controls performed the STA and the Wisconsin Card Sorting Test (WCST), respectively, as well as several other traditional neuropsychological tests and the Symbol Digit Substitution Test (SDST) on a writing digitizer.The STA correlated only weakly with the WCST and SDST measures but not with the cognitive or motor slowing on the SDST, nor with the other cognitive measures. Stereotyped and perseverative idiosyncrasies both seem to increase in the course of the illness, in contrast with other cognitive dysfunctions. However, whereas perseveration is already present in the early stages of the illness, stereotyped behaviour only manifests itself in the later stages of schizophrenia. Failure of cognitive inhibition may result in an activation of prepotent stereotyped responses captured by the STA.

The present analysis investigated symptomspecific dose-response relationships of the atypical antipsychotic amisulpride (AMI) in schizophrenic patients. The effects of different AMI doses on five different symptom dimensions of the Brief Psychiatric Rating Scale (BPRS) were analyzed. Results on global efficacy and safety parameters have been previously published. Four AMI doses (100 mg/day [AMI100], 400 mg/day [AMI400], 800 mg/day [AMI800], 1200 mg/day) were compared with 16 mg haloperidol (HAL16) in a multicenter, double-blind, randomized, parallel-group, 4-week trial. A total of 319 patients with acute exacerbation of schizophrenia (DSM-III-R) were included. AMI100 was compared with the other AMI doses, and HAL16 was compared with all AMI dosage groups. Response on BPRS factors defined as ≥ 40% improvement and ORs were computed. An optimal AMI dose was calculated for each BPRS factor based on linear and quadratic regression. For all BPRS factors, inverted u-shaped dose-response curves emerged (r2 > 95%). The estimated AMI dose optimum for the BPRS factors activation/ agitation (760 mg), thought disturbances (716 mg), and hostility/suspiciousness (694 mg) was higher than that for anergia/negative symptoms (584 mg) and depression/anxiety (672 mg). Significant differences (p < 0.05) were found for AMI400/800 versus AMI100 (thought disturbances, hostility/ suspiciousness), for AMI400/800 versus HAL16 (depression/anxiety, thought disturbances, hostility/suspiciousness), and for AMI400 versus HAL16 (anergia/negative symptoms). ORs for response of the BPRS factors depression/anxiety, anergia/negative symptoms, and hostility/suspiciousness were highest under treatment with AMI400 compared to AMI100 and HAL16. For the BPRS factors thought disturbances and activation/agitation, the highest response chance emerged under AMI800 compared to AMI100 or HAL16. AMI seems to show the best clinical efficacy in acutely schizophrenic patients in a moderate dose (400–800 mg/day), with a somewhat lower dose optimum for negative than for positive symptoms. The present finding of distinct dose-response relationships of AMI regarding the BPRS dimensions is in accordance with studies on the mechanism of action of AMI and provides a useful rationale for the clinical treatment of schizophrenic patients with AMI.

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Over the last 50 years, patient autonomy has become an increasingly important part of the principles of medical ethics, or rather of the ethics of the doctor-patient relationship. While the principle of charity and the associated paternalism became less important, the patient's active consent became more and more relevant (Sass, 1989; Bayer, 1998; Nedopil, 1998). This development was inevitably also accompanied by a demand for more detailed information prior to medical interventions (Appelbaum and Grisso, 1988; Weisstub, 1990; Kreussler, 1997; Ulsenheimer, 1995; Laufs, 1997; Sommer, 1997) and for complete information on medical procedures subsequent to interventions (e. g. Bender, 1997). Determination of a person's competence to give informed consent is a central problem in the assessment of his expression of consent to a medical intervention. The capacity to adequately express consent can be impaired at certain stages of life and during some illnesses. Patients in borderline situations, children, mentally ill patients and old people with dementia may either be limited in their capacity to give informed consent, or be completely unable to do so. This results in special ethical problems when such groups are included in research projects.

There is little agreement about the methodology of clinical trials of antipsychotic drugs in patients with negative symptoms. A literature review revealed wide variation in experimental design, rating scales and study duration. This reflects differing views as to the definition and response to treatment of negative symptoms. Some degree of standardization would improve comparability of studies and aid the development of new compounds. Patients included in such studies should have displayed negative symptoms for at least 6 months. Depressive symptoms, positive schizophrenic symptoms and extrapyramidal signs may all influence or be confused with negative symptoms and may respond to treatment; they should be at a low level at baseline and should be measured during the study period. Studies should last at least 8 weeks. Several scales are available for measuring negative symptoms and are reviewed; a global impression score should be used additionally.

The effects of 20 mg zolipidem were studied in an open, polysomnographically-monitored 179 day trial in 14 elderly psychiatric patients suffering from severe insomnia. After a placebo run-in of 7 days, zolpidem was given for 179 days followed by a 30-day wash-out period. Polysomnographic recordings (PSG) were performed just before active treatment; 30, 90 and 179 days into the treatment period; and at the end of the wash-out period. Statistically significant improvements in total sleep time, sleep efficiency and percentage of rapid eye movement sleep were observed after 30 days, all of which were maintained at 179 days. Sleep stages 1-4 all changed, with a significant decrease in percentage of stage 1, and a significant increase in both percentages of stage 2 and 3, and duration of stages 3 and 4 at the end of active treatment. After a 90-day follow-up period, only stage 3 sleep and sleep efficiency were no longer significantly changed compared to baseline, all other criteria showing maintenance of efficacy. Slow-wave sleep, which was increased during active treatment, decreased in the follow-up period. No serious adverse events were observed. These results suggest that, contrary to other hypnotics, zolpidem, after long-term administration, improves objective sleep parameters and may normalize a disturbed sleep architecture.

In a pilot double-blind trial in 21 patients with learned or idiopathic insomnia (DSM-IIIR), patients received placebo for 1 week (nights 1 - 7), either active (zolpidem, 10 mg) or placebo treatment for 2 weeks (nights 8 - 21) and then placebo for a further week (nights 22 - 28). Variables to measure efficacy, rebound and withdrawal were assessed daily from day 1 to day 28. Polysomnographic recordings together with sleep cycle analysis were performed on nights 7, 21 and 28. Patients treated with 10 mg zolpidem for 2 weeks had significantly improved sleep efficiency at the end of the randomised double-blind phase compared with the placebo group. Fractionated sleep-cycle analysis showed an increase in slow-wave sleep during the first 2-hour cycle after sleep onset. During the withdrawal placebo week, most of the main sleep variables remained relatively stable in the zolpidem group (nights 22 - 28), and deteriorated further in the placebo group. At the end of the withdrawal phase, there was a statistically significant difference between groups, in favour of the zolpidem treatment, in sleep efficiency, total sleep time, absolute and percentage of time awake, and percentage of REM sleep. REM sleep, which was normal in both groups at baseline, decreased significantly in the placebo group between nights 22 and 28 (during the withdrawal placebo week) compared with the zolpidem treatment group, and the number of periods of time awake increased. Minor subjective complaints were recorded under zolpidem and were comparable with those under placebo. Zolpidem seemed to improve some important sleep variables, when assessed both objectively and subjectively. The sleep cycle analysis suggested a possible shift of slow-wave sleep to an earlier period of the night, with a more physiological sleep structure. There was no evidence for withdrawal or rebound after stopping the 2 weeks of zolpidem treatment, but rather signs that the effect of zolpidem outlasted active treatment. The present pilot study justifies a prospective confirmatory comparison of zolpidem with benzodiazepines in an adequate number of patients and withdrawal after 6 - 8 weeks of treatment.